I have been studying the biology of the response of the yeast Saccharomyces cerevisiae to DNA alkylation damage. Alkylating agents represent the most abundant class of chemical DNA damaging agents in the environment and they are even present as natural cellular metabolites. These agents are cable of inducing cell death, mutation, chromosomal damage and cancer. Since humans are continuously exposed to these chemicals, and since some alkylating agents are clinically useful chemotherapeutic agents, it is important to understand exactly how cells respond to these agents. Organisms as diverse as bacteria, yeast and mammalian have developed highly conserved mechanism for the repair of damage caused by many reactive environmental and endogenous compounds. I plan to identify new pathways that protect cells against alkylating agents to enhance our understanding of the eukaryotic response to DNA damage. The specific aims include the following: using DNA chip technology, identify and isolate new eukaryotic genes involved in the response of cells to alkylation damage and to identify those that are coordinately regulated; determine whether and how the inducible genes protect against alkylation damage; identify regulatory elements responsible for increased transcription. S. cerevisiae possess regulated systems of gene expression that respond to DNA damage and these studies should greatly enhance our understanding of these responses.